The mechanisms of how growth cones integrate simultaneous guidance instructions or how they modify responsiveness to sequential cues along their trajectories have not been well understood. Our preliminary study revealed a novel gene-expression-based switch mechanism. Our previous work showed that planar cell polarity (PCP) signaling is essential for their proper anterior-posterior (A-P) guidance after midline crossing. We now found that Sonic Hedgehog (Shh) induces a subset of PCP genes in commissural neurons during midline crossing. We propose that this novel regulatory loop between Shh and PCP signaling may also be essential in many other cases of axon guidance or in developmental processes other than axon guidance. In this exploratory R21 grant, we propose to understand the mechanisms of how Shh-Smo signaling activates the PCP gene expression.